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mTORC1 is an important regulator of cell growth and cell proliferation and its activity is adjusted in response to multiple cues including oxygen levels. Under conditions of hypoxia, mTORC1 is inhibited. Hypoxia-induced mTORC1 inhibition typically involves the REDD1 protein. REDD1 is transcriptionally induced in response to hypoxia, and in fibroblasts and many other cell types, REDD1 is necessary for mTORC1 inhibition by hypoxia. Moreover, REDD1 overexpression is sufficient to inhibit mTORC1. REDD1 is a member of a family that includes also REDD2, which appears to have arisen through a gene duplication event occurring independently in insects and humans. REDD1 is a 25 kDa protein with no known structural or functional domains, and a novel structural fold. Despite that hypoxia would predictably lead over time to decreased energy stores, mTORC1 inhibition by hypoxia can occur independently of the energy signaling kinases AMPK and LKB1. REDD1-induced mTORC1 inhibition requires a functional TSC1/TSC2 complex and can be blocked by Rheb overexpression, but how REDD1 signals remains to be elucidated. The TSC1/TSC2 complex is also required for mTORC1 inhibition by hypoxia in many cell types and failure to downregulate mTORC1 in TSC1/TSC2-deficient fibroblasts in response to hypoxia results in increased cell proliferation. How tumors sustain mTORC1 activity despite hypoxia remains to be elucidated, but in normal cells, the downregulation of mTORC1 by hypoxia likely represents an adaptative mechanism whereby energy demanding processes, such as protein translation, are downregulated. [ABSTRACT FROM AUTHOR]